COMPARATIVE MOUSE SKIN TUMORIGENICITY AND INDUCTION OF HA-RAS MUTATIONS BY BAY-REGION DIOL EPOXIDES OF 5-METHYLCHRYSENE AND 5,6-DIMETHYLCHRYSENE

We compared the tumor-initiating activities toward mouse skin of two s tructurally related polycyclic aromatic hydrocarbon diol epoxides: rac emic trahydro-5,6-dimethylchrysene-1,2-diol-3,4-epoxide (5,6-diMeCDE) and racemic 4-tetrahydro-5-methylchrysene-1,2-diol-3,4-epoxide (5-MeCD E). Tumors induced by these diol epoxides were analysed for mutations in the Ha-ras gene. 5,6-diMeCDE is derived from the non-planar parent compound 5,6-dimethylchrysene, and reacts to approximately equal exten ts with dA and dG in DNA, whereas 5-MeCDE is derived from a nearly pla nar parent compound, 5-methylchrysene, and reacts mainly with dG in DN A, 5,6-diMeCDE, at initiating doses of 33, 100 or 400 nmol per mouse, induced 1.2, 2.2 and 6.2 skin tumors per mouse, respectively. It was s ignificantly less tumorigenic than 5-MeCDE which induced 3.1, 7.5 and 9.1 skin tumors per mouse at the same doses, Tumors induced by 5,6-diM eCDE had a large number of CAA-->CTA mutations in codon 61 of the Ha-r as gene: 50, 55 and 75% of the tumors analysed had this mutation at th e 33, 100 and 400 nmol doses. No mutations were found in codons 12 and 13 in the tumors induced by 5,6-diMeCDE, In contrast, CAA-->CTA mutat ions in codon 61 were rarely seen in tumors induced by 5-MeCDE. At the highest dose of 5-MeCDE, 20% of the tumors analysed had mutations at G of codons 12 and 13. The results of this comparative study support t he hypothesis that mutations in the Ha-ras gene in mouse skin tumors i nduced by PAH diol epoxides occur as a result of their direct reaction with the gene. However, pathways other than the commonly observed Ha- ras codon 61 mutations are clearly important in mouse skin tumorigenes is by these diol epoxides.